tbuckley/cabot-search huggingface dataset:
Abstract 16908: CTX310: An Investigational <i>in vivo</i> CRISPR-Based Therapy Efficiently and Durably Reduces ANGPTL3 Protein and Triglyceride Levels in Non-Human Primates After a Single Dose
Authors: Phuong Khanh Morrow, Yi-Shan Chen, Laura Serwer, Zachary Detwiler, Nicole Flanagan, Elizabeth Koch, Maria Lei Zhang, Michelle Mu, Thao Nguyen, Erisa Sula, Erin Thorstensen, Samuel Tomp, Kayla Urbaez, Jacob Usadi, Li Wang, Kaitlin Watrud, Tess Wood, Xuezhi Zhang
Journal: Circulation (2023)

Background: Angiopoietin-like 3 (ANGPTL3) is a key regulator of lipid metabolism. In humans, naturally occurring loss-of-function variants in ANGPTL3 are associated with reduced levels of serum lipids and reduced risk of atherosclerotic cardiovascular disease. CTX310™ is an investigational in vivo CRISPR/Cas9 gene editing therapy designed to knock out hepatic expression of ANGPTL3. CTX310 consists of Cas9 mRNA and guide RNA (gRNA) targeting ANGPTL3 encapsulated into lipid nanoparticles (LNPs). Here we assessed the efficacy, safety, and durability of CTX310 in primary human cells, mice, and non-human primates (NHPs). Methods: CTX310 was evaluated in vitro in primary human hepatocytes (PHHs), in vivo in wildtype C57BL/6J and LDLR-/- mice using a mouse surrogate gRNA, and in vivo in NHPs where the human target sequence is conserved. For the NHP studies, cynomolgus monkeys were infused with a single dose of CTX310 at doses ranging from 0.5 to 3.0 mg/kg to evaluate efficacy (N=32) and durability (N=8). Results: In PHHs, &gt;90% on-target editing was achieved with CTX310, leading to a &gt;90% reduction in ANGPTL3 production. Comprehensive genomic assessment indicated no sign of unintended genomic changes introduced by CTX310. In wildtype mice administered LNPs containing a mouse surrogate gRNA along with the same Cas9 mRNA and lipid components as CTX310, ~50% liver editing yielded a &gt;95% reduction in plasma ANGPTL3 protein and ~40% reduction in triglyceride levels, sustained up to nine months post-dosing. Similar levels of editing and efficacy were observed in LDLR-/- mice, suggesting an LDLR-independent uptake mechanism.In NHPs, dose-dependent editing of ANGPTL3 in the liver of up to 71% was observed, resulting in reduced levels of plasma ANGPTL3 protein (up to 86%) and triglycerides (up to 64%). Reductions in ANGPTL3 protein and triglycerides were durable past 32 weeks. As is commonly observed with LNP delivery, transient elevation of liver enzymes was observed and resolved within 14 days without intervention. Conclusion: CTX310 was well-tolerated in NHPs and led to significant and durable reductions in circulating ANGPTL3 and triglycerides. This data suggests that CTX310 could be used to treat dyslipidemias in humans.
Predictive analytics for cardio-thoracic surgery duration as a stepstone towards data-driven capacity management
Authors: Mariana Nikolova-Simons, Rikkert Keldermann, Yvon Peters, Wilma Compagner, Leon Montenij, Ymke de Jong, R. Arthur Bouwman
Journal: npj Digital Medicine (2023)

Abstract Effective capacity management of operation rooms is key to avoid surgery cancellations and prevent long waiting lists that negatively affect clinical and financial outcomes as well as patient and staff satisfaction. This requires optimal surgery scheduling, leveraging essential parameters like surgery duration, post-operative bed type and hospital length-of-stay. Common clinical practice is to use the surgeon’s average procedure time of the last N patients as a planned surgery duration for the next patient. A discrepancy between the actual and planned surgery duration may lead to suboptimal surgery schedule. We used deidentified data from 2294 cardio-thoracic surgeries to first calculate the discrepancy of the current model and second to develop new predictive models based on linear regression, random forest, and extreme gradient boosting. The new ensamble models reduced the RMSE for elective and acute surgeries by 19% (0.99 vs 0.80, p = 0.002) and 52% (1.87 vs 0.89, p &lt; 0.001), respectively. Also, the elective and acute surgeries “behind schedule” were reduced by 28% (60% vs. 32%, p &lt; 0.001) and 9% (37% vs. 28%, p = 0.003), respectively. These improvements were fueled by the patient and surgery features added to the models. Surgery planners can benefit from these predictive models as a patient flow AI decision support tool to optimize OR utilization.
Artificial intelligence-based pathology as a biomarker of sensitivity to atezolizumab–bevacizumab in patients with hepatocellular carcinoma: a multicentre retrospective study
Authors: Qinghe Zeng, Christophe Klein, Stefano Caruso, Pascale Maille, Daniela S Allende, Beatriz Mínguez, Massimo Iavarone, Massih Ningarhari, Andrea Casadei-Gardini, Federica Pedica, Margherita Rimini, Riccardo Perbellini, Camille Boulagnon-Rombi, Alexandra Heurgué, Marco Maggioni, Mohamed Rela, Mukul Vij, Sylvain Baulande, Patricia Legoix, Sonia Lameiras, Daniela S Allende, Giuliana Amaddeo, Josepmaria Argemi, Sylvain Baulande, Aurélie Beaufrère, María Bermúdez-Ramos, Camille Boulagnon-Rombi, Jérôme Boursier, Léa Bruges, Julien Calderaro, Claudia Campani, Stefano Caruso, Andrea Casadei-Gardini, Andres Castano Garcia, Stephen Lam Chan, Antonio D'Alessio, Luca Di Tommaso, Alba Diaz, Antonia Digklia, Jean-François Dufour, Guillermo Garcia-Porrero, Narmin Ghaffari Laleh, Viviane Gnemmi, Purva Gopal, Rondell P. Graham, Alexandra Heurgué, Massimo Iavarone, Mercedes Iñarrairaegui, Jakob Nikolas Kather, Christophe Klein, Ismail Labgaa, Sonia Lameiras, Patricia Legoix, Marie Lequoy, Howard Ho-Wai Leung, Nicolas Loménie, Marco Maggioni, Pascale Maille, Juan Ignacio Marín-Zuluaga, Guillermo Mendoza-Pacas, Sophie Michalak, Beatriz Mínguez, Omar S M El Nahhas, Jean-Charles Nault, Pooja Navale, Massih Ningarhari, Valérie Paradis, Young Nyun Park, Jean-Michel Pawlotsky, Federica Pedica, Riccardo Perbellini, Simon Peter, David James Pinato, Matthias Pinter, Pompilia Radu, Hélène Regnault, Maria Reig, Mohamed Rela, Hyungjin Rhee, Lorenza Rimassa, Margherita Rimini, María Teresa Salcedo, Bruno Sangro, Bernhard Scheiner, Christine Sempoux, Tung-Hung Su, Callie Torres, Nguyen H Tran, Eric Trépo, Maria Varela, Gontran Verset, Mukul Vij, Arndt Vogel, Dominique Wendum, Qinghe Zeng, Marianne Ziol, Léa Bruges, Viviane Gnemmi, Jean-Charles Nault, Claudia Campani, Hyungjin Rhee, Young Nyun Park, Mercedes Iñarrairaegui, Guillermo Garcia-Porrero, Josepmaria Argemi, Bruno Sangro, Antonio D'Alessio, Bernhard Scheiner, David James Pinato, Matthias Pinter, Valérie Paradis, Aurélie Beaufrère, Simon Peter, Lorenza Rimassa, Luca Di Tommaso, Arndt Vogel, Sophie Michalak, Jérôme Boursier, Nicolas Loménie, Marianne Ziol, Julien Calderaro
Journal: The Lancet Oncology (2023)
Diphtheria outbreak in Nigeria
Authors: Vijay Shankar Balakrishnan
Journal: The Lancet Microbe (2023)

At a Médecins Sans Frontières (MSF) hospital in Kano, Nigeria, Dr Hashim Juma Omar encounters at least six children daily with diphtheria symptoms, including the characteristic throat patches, swollen lymph nodes, fever, fatigue, and chills. "I've never seen [so] many serious diphtheria cases this frequently in my career," Omar tells The Lancet Microbe. "Not just at our MSF hospital, but many in the region are seeing a flurry of patients, both children and adults, but the most at-risk being kids".
The Lancet Commission on medicine, Nazism, and the Holocaust: historical evidence, implications for today, teaching for tomorrow
Authors: Herwig Czech, Sabine Hildebrandt, Shmuel P Reis, Tessa Chelouche, Matthew Fox, Esteban González-López, Etienne Lepicard, Astrid Ley, Miriam Offer, Avi Ohry, Maike Rotzoll, Carola Sachse, Sari J Siegel, Michal Šimůnek, Amir Teicher, Kamila Uzarczyk, Anna von Villiez, Hedy S Wald, Matthew K Wynia, Volker Roelcke
Journal: The Lancet (2023)
Extracellular vesicles encapsulated with caspase-1 inhibitor ameliorate experimental autoimmune myasthenia gravis through targeting macrophages
Authors: Yang Zhou, Tong Du, Chun-Lin Yang, Tao Li, Xiao-Li Li, Wei Liu, Peng Zhang, Jing Dong, Wei-Yue Si, Rui-Sheng Duan, Cong-Cong Wang
Journal: Journal of Controlled Release (2023)

Cysteinyl aspartate-specific proteinase-1 (caspase-1) is a multifunctional inflammatory mediator in many inflammation-related diseases. Previous studies show that caspase-1 inhibitors produce effective therapeutic outcomes in a rat model of myasthenia gravis. However, tissue toxicity and unwanted off-target effects are the major disadvantages limiting their clinical application as therapeutic agents. This study shows that dendritic cell-derived extracellular vesicles (EVs) loaded with a caspase-1 inhibitor (EVs-VX-765) are phagocytized mainly by macrophages, and caspase-1 is precisely expressed in macrophages. Furthermore, EVs-VX-765 demonstrates excellent therapeutic effects through a macrophage-dependent mechanism, and it notably inhibits the level of interleukin-1β and subsequently inhibits Th17 response and germinal center (GC) reactions. In addition, EVs-VX-765 demonstrates better therapeutic effects than routine doses of VX-765, although drug loading is much lower than routine doses, consequently reducing tissue toxicity. In conclusion, this study's findings suggest that EV-mediated delivery of caspase-1 inhibitors is effective for treating myasthenia gravis and is promising for clinical applications.
Mechanism and therapeutic potential of targeting cGAS-STING signaling in neurological disorders
Authors: Yige Huang, Bangyan Liu, Subhash C. Sinha, Sadaf Amin, Li Gan
Journal: Molecular Neurodegeneration (2023)

Abstract DNA sensing is a pivotal component of the innate immune system that is responsible for detecting mislocalized DNA and triggering downstream inflammatory pathways. Among the DNA sensors, cyclic GMP-AMP synthase (cGAS) is a primary player in detecting cytosolic DNA, including foreign DNA from pathogens and self-DNA released during cellular damage, culminating in a type I interferon (IFN-I) response through stimulator of interferon genes (STING) activation. IFN-I cytokines are essential in mediating neuroinflammation, which is widely observed in CNS injury, neurodegeneration, and aging, suggesting an upstream role for the cGAS DNA sensing pathway. In this review, we summarize the latest developments on the cGAS-STING DNA-driven immune response in various neurological diseases and conditions. Our review covers the current understanding of the molecular mechanisms of cGAS activation and highlights cGAS-STING signaling in various cell types of central and peripheral nervous systems, such as resident brain immune cells, neurons, and glial cells. We then discuss the role of cGAS-STING signaling in different neurodegenerative conditions, including tauopathies, Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, as well as aging and senescence. Finally, we lay out the current advancements in research and development of cGAS inhibitors and assess the prospects of targeting cGAS and STING as therapeutic strategies for a wide spectrum of neurological diseases.
Statement on the Lancet Commission on Medicine, Nazism, and the Holocaust
Authors: Tessa Chelouche, Herwig Czech, Matthew A Fox, Sabine Hildebrandt, Etienne Lepicard, Astrid Ley, Miriam Offer, Avi Ohry, Shmuel P Reis, Volker Roelcke, Maike Rotzoll, Carola Sachse, Sari J Siegel, Michal Šimůnek, Amir Teicher, Kamila Uzarczyk, Anna von Villiez, Hedy S Wald, Matthew K Wynia
Journal: The Lancet (2023)
Osimertinib with or without Chemotherapy in <i>EGFR</i> -Mutated Advanced NSCLC
Authors: David Planchard, Pasi A. Jänne, Ying Cheng, James C.-H. Yang, Noriko Yanagitani, Sang-We Kim, Shunichi Sugawara, Yan Yu, Yun Fan, Sarayut L. Geater, Konstantin Laktionov, Chee K. Lee, Natalia Valdiviezo, Samreen Ahmed, Jean-Marc Maurel, Igor Andrasina, Jonathan Goldman, Dana Ghiorghiu, Yuri Rukazenkov, Alex Todd, Kunihiko Kobayashi
Journal: New England Journal of Medicine (2023)

Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that is selective for EGFR-TKI-sensitizing and
Severe Immune-Related Enteritis after In Utero Exposure to Pembrolizumab
Authors: Manuel A. Baarslag, Joosje H. Heimovaara, Jessica S.W. Borgers, Koen J. van Aerde, Hans J.P.M. Koenen, Ruben L. Smeets, Pauline L.M. Buitelaar, Dick Pluim, Shoko Vos, Stefanie S.V. Henriet, Jan Willem B. de Groot, Martine van Grotel, Hilde Rosing, Jos H. Beijnen, Alwin D.R. Huitema, John B.A.G. Haanen, Frédéric Amant, Nicole Gierenz
Journal: New England Journal of Medicine (2023)

Immune checkpoint blockade has become standard treatment for many types of cancer. Such therapy is indicated most often in patients with advanced or metastatic disease but has been increasingly used as adjuvant therapy in those with early-stage disease. Adverse events include immune-related organ inflammation resembling autoimmune diseases. We describe a case of severe immune-related gastroenterocolitis in a 4-month-old infant who presented with intractable diarrhea and failure to thrive after in utero exposure to pembrolizumab. Known causes of the symptoms were ruled out, and the diagnosis of pembrolizumab-induced immune-related gastroenterocolitis was supported by the results of histopathological assays, immunophenotyping, and analysis of the level of antibodies against programmed cell death protein 1 (PD-1). The infant's condition was successfully treated with prednisolone and infliximab.
Randomized Trial of Hyperimmune Globulin for Congenital CMV Infection — 2-Year Outcomes
Authors: Brenna L Hughes, Rebecca G Clifton, Dwight J Rouse, George R Saade, Mara J Dinsmoor, Uma M Reddy, Robert Pass, Donna Allard, Gail Mallett, Cora MacPherson, Ronald Wapner, Torri Metz, William H Goodnight, Alan T N Tita, Maged M Costantine, Geeta K Swamy, Kent D Heyborne, Edward K Chien, Suneet P Chauhan, Yasser Y El-Sayed, Brian M Casey, Samuel Parry, Hyagriv N Simhan, Peter G Napolitano, George A Macones
Journal: New England Journal of Medicine (2023)
Actionable Genotypes and Their Association with Life Span in Iceland
Authors: Brynjar O. Jensson, Gudny A. Arnadottir, Hildigunnur Katrinardottir, Run Fridriksdottir, Hannes Helgason, Asmundur Oddsson, Gardar Sveinbjornsson, Hannes P. Eggertsson, Gisli H. Halldorsson, Bjarni A. Atlason, Hakon Jonsson, Gudjon R. Oskarsson, Arni Sturluson, Sigurjon A. Gudjonsson, Gudmundur A. Thorisson, Florian Zink, Kristjan H.S. Moore, Gunnar Palsson, Asgeir Sigurdsson, Adalbjorg Jonasdottir, Aslaug Jonasdottir, Magnus K. Magnusson, Anna Helgadottir, Valgerdur Steinthorsdottir, Julius Gudmundsson, Simon N. Stacey, Rafn Hilmarsson, Isleifur Olafsson, Oskar T. Johannsson, David O. Arnar, Jona Saemundsdottir, Olafur T. Magnusson, Gisli Masson, Bjarni V. Halldorsson, Agnar Helgason, Hreinn Stefansson, Ingileif Jonsdottir, Hilma Holm, Thorunn Rafnar, Unnur Thorsteinsdottir, Daniel F. Gudbjartsson, Kari Stefansson, Patrick Sulem
Journal: New England Journal of Medicine (2023)

In 2021, the American College of Medical Genetics and Genomics (ACMG) recommended reporting actionable genotypes in 73 genes associated with diseases for which preventive or therapeutic measures are available. Evaluations of the association of actionable genotypes in these genes with life span are currently lacking. We assessed the prevalence of coding and splice variants in genes on the ACMG Secondary Findings, version 3.0 (ACMG SF v3.0), list in the genomes of 57,933 Icelanders. We assigned pathogenicity to all reviewed variants using reported evidence in the ClinVar database, the frequency of variants, and their associations with disease to create a manually curated set of actionable genotypes (variants). We assessed the relationship between these genotypes and life span and further examined the specific causes of death among carriers. Through manual curation of 4405 sequence variants in the ACMG SF v3.0 genes, we identified 235 actionable genotypes in 53 genes. Of the 57,933 participants, 2306 (4.0%) carried at least one actionable genotype. We found shorter median survival among persons carrying actionable genotypes than among noncarriers. Specifically, we found that carrying an actionable genotype in a cancer gene was associated with survival that was 3 years shorter than that among noncarriers, with causes of death among carriers attributed primarily to cancer-related conditions. Furthermore, we found evidence of association between carrying an actionable genotype in certain genes in the cardiovascular disease group and a reduced life span. On the basis of the ACMG SF v3.0 guidelines, we found that approximately 1 in 25 Icelanders carried an actionable genotype and that carrying such a genotype was associated with a reduced life span. (Funded by deCODE Genetics–Amgen.)
Effects of a Web-Based Behavioral Activation Intervention on Depressive Symptoms, Activation, Motivation, and Volition: Results of a Randomized Controlled Trial
Authors: Claudia Mueller-Weinitschke, Jürgen Bengel, Harald Baumeister, Lena Violetta Krämer
Journal: Psychotherapy and Psychosomatics (2023)

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Behavioral activation (BA) is effective for the treatment of depression. The Health Action Process Approach (HAPA), which is derived from health psychology, can provide a motivational-volitional framework of BA. &lt;b&gt;&lt;i&gt;Objective:&lt;/i&gt;&lt;/b&gt; This study investigated the efficacy of a HAPA-based internet-delivered BA intervention (iBA; called InterAKTIV) in individuals with depression, also assessing HAPA-based motivational and volitional outcomes. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; In a two-arm randomized controlled efficacy trial with a parallel design, 128 participants with a major depressive episode were randomly allocated to the intervention group (IG; TAU + immediate access to iBA) or control group (CG; TAU + access to iBA after follow-up). The primary outcome of clinician-rated depressive symptoms and secondary outcomes were assessed at baseline (T1), 8 weeks (T2), 6-month after randomization (T3). Data were analyzed on an intention-to-treat basis. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Linear mixed model analyses revealed a significant group*time interaction effect on clinician-rated depressive symptoms favoring the IG (F&lt;sub&gt;2, 156.0&lt;/sub&gt; = 7.40; &lt;i&gt;p&lt;/i&gt; &amp;lt; 0.001, &lt;i&gt;d&lt;/i&gt; = 0.79 at T2, &lt;i&gt;d&lt;/i&gt; = 0.25 at T3). The IG was also superior regarding self-rated depressive symptoms, BA, most motivational, and all volitional outcomes. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; This study shows that HAPA-based iBA can significantly improve clinician-rated depressive symptoms, as well as outcomes used in the HAPA model in people with depression. Building on these efficacy results, in the next step, the relationship between BA interventions and activity levels should be investigated, taking into account motivation and volition as potential mediators.
Case 34-2023: A 49-Year-Old Woman with Loss of Consciousness and Thrombocytopenia
Authors: Kori S. Zachrison, Shahmir Kamalian, David B. Sykes, Patricia A.R. Brunker
Journal: New England Journal of Medicine (2023)

A 49-year-old woman was found unconscious at work. Evaluation was notable for aphasia, apraxia, and marked thrombocytopenia and anemia. A diagnosis was made.
Universal Decolonization in Nursing Homes — Apparent Benefits but Feasible?
Authors: Morgan J. Katz, Sara E. Cosgrove
Journal: New England Journal of Medicine (2023)

Nursing homes house a population most at risk for prolonged colonization with multidrug resistant organisms (MDROs) owing to the residents' older age, repeat health care and antibiotic exposures, and ongoing contact with other persons with colonization.1 Although nursing homes pose a perfect opportunity for the cultivation and continued transmission of MDROs, decolonization efforts in this setting have been minimal, probably because of the real challenges of implementing decolonization in nursing homes. On account of limited resources, few nursing homes perform active surveillance for MDROs2; rather, they rely on often incomplete reports from the transferring hospital, which makes targeted decolonization based . . .
Trial of Botulinum Toxin for Isolated or Essential Head Tremor
Authors: Ana Marques, Bruno Pereira, Marion Simonetta-Moreau, Giovanni Castelnovo, Marie De Verdal, Frédérique Fluchère, Chloé Laurencin, Bertrand Degos, Mélissa Tir, Alexandre Kreisler, Geneviève Blanchet-Fourcade, Dominique Guehl, Olivier Colin, Aurelia Poujois, Sophie Sangla, Laurent Tatu, Philippe Derost, Dominique Gayraud, Christine Tranchant, David Amarantini, David Devos, Olivier Rascol, Jean-Christophe Corvol, Franck Durif, Isabelle Rieu
Journal: New England Journal of Medicine (2023)

Local injections of botulinum toxin type A have been used to treat essential head tremor but have not been extensively studied in randomized trials. In a multicenter, double-blind, randomized trial, we assigned, in a 1:1 ratio, adult patients with essential or isolated head tremor to receive botulinum toxin type A or placebo. Botulinum toxin or placebo was injected under electromyographic guidance into each splenius capitis muscle on the day of randomization (day 0) and during week 12. The primary outcome was improvement by at least 2 points on the Clinical Global Impression of Change (CGI) scale at week 6 after the second injection (week 18 after randomization). The CGI scale was used to record the patient's assessment of the degree of improvement or worsening of head tremor since baseline; scores range from 3 (very much improved) to -3 (very much worse). Secondary outcomes included changes in tremor characteristics from baseline to weeks 6, 12, and 24. A total of 120 patients were enrolled; 3 patients were excluded during screening, and 117 patients were randomly assigned to receive botulinum toxin (62 patients) or placebo (55 patients) and were included in the intention-to-treat analysis. Twelve patients in the botulinum toxin group and 2 patients in the placebo group did not receive injections during week 12. The primary outcome - improvement by at least 2 points on the CGI scale at week 18 - was met by 31% of the patients in the botulinum toxin group as compared with 9% of those in the placebo group (relative risk, 3.37; 95% confidence interval, 1.35 to 8.42; P = 0.009). Analyses of secondary outcomes at 6 and 12 weeks but not at 24 weeks were generally supportive of the primary-outcome analysis. Adverse events occurred in approximately half the patients in the botulinum toxin group and included head and neck pain, posterior cervical weakness, and dysphagia. Injection of botulinum toxin into each splenius capitis muscle on day 0 and during week 12 was more effective than placebo in reducing the severity of isolated or essential head tremor at 18 weeks but not at 24 weeks, when the effects of injection might be expected to wane, and was associated with adverse events. (Funded by the French Ministry of Health; Btx-HT ClinicalTrials.gov number, NCT02555982.).
Reply to Gan <i>et al.</i>, to Calzetta <i>et al.</i>, and to Poor
Authors: Antonio Anzueto, Igor Z. Barjaktarevic, Thomas M Siler, Tara Rheault, Thomas Bengtsson, Kathleen Rickard, Frank Sciurba
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Reply to Gan et al., to Calzetta et al., and to Poor." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.